The twelve known carbonic anhydrases (CAs) and CA-related proteins (CA- RPs) play important roles in diverse physiological processes including respiration, bone resorption, renal acidification, gluconeogenesis, signal transduction, and formation of cerebrospinal fluid and gastric acid. The recently discovered CA IX and CA XII are related to oncogenesis and are over-expressed in certain cancers. The broad goal of this research is to study the functional genomics of this gene family to determine the importance of individual members to health and disease. We have five specific aims: 1. Complete studies characterizing the biochemical and molecular genetics of CA II deficiency. CA II deficiency is the basis for the human inborn error of metabolism producing osteopetrosis, renal tubular acidosis, and brain calcification, novel studies are also proposed on the CA II-deficient mouse. 2. Characterize the mouse doubly deficient for CA II and CA IV and determine what other CA in kidney compensates for CA IV deficiency. CA IV is the GPI-anchored membrane CA on surfaces of epithelial cells in kidney and gut and of capillary endothelial cells. The CA IV null mouse lacks the expected renal defect. 3. Characterize the CA VA gene knockout mouse, the newly discovered CA Vb, and candidates for CA V deficiency. CA VA is the mitochondrial CA thought to be involved in gluconeogenesis and ureagenesis. 4. Characterize CA IX and define its role in the regulation of cell proliferation and in oncogenesis. CA IX is a tumor-associated CA that is over-expressed in several cancers and expressed in normal stomach. 5. Characterize the properties and the functional genomics of CA XII. CA XII is a newly discovered, transmembrane CA that is over-expressed in several cancers and expressed in normal kidney and intestine. These studies should enhance our understanding of how thee individual carbonic anyhydrases contribute to normal physiology, how single CA deficiencies produce disease, and why the newly discovered CAs IX and XII are over-expressed in certain cancers, and should also suggest new targets for isozyme-specific CA inhibitors.